Method for increasing the bioavailability of glycopyrrolate

ABSTRACT

The invention relates to a method of increasing the bioavailability of glycopyrrolate by administration of a therapeutically effective amount of glycopyrrolate without food. The invention also provides a kit comprising a pharmaceutical composition comprising a therapeutically effective amount of glycopyrrolate and a pharmaceutically acceptable carrier, prescribing information including advice regarding the administration of glycopyrrolate without food to improve bioavailability, and a container.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of copending U.S. patent applicationSer. No. 11/586,837, filed on Oct. 26, 2006, which is a divisional ofcopending U.S. patent application Ser. No. 11/334,020, filed on Jan. 18,2006, which is a divisional of U.S. patent application Ser. No.10/644,530, filed on Aug. 20, 2003, now U.S. Pat. No. 7,091,236.

FIELD OF THE INVENTION

The invention relates to methods for increasing the bioavailability ofdrug products containing glycopyrrolate.

BACKGROUND OF THE INVENTION

Glycopyrrolate, the active pharmaceutical ingredient in Robinul®tablets, Robinul® Forte tablets and Robinul® injection, is a quaternaryammonium compound having the chemical name3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidiniumbromide. Glycopyrrolate is an anticholinergic and antispasmodic thatinhibits gastrointestinal nerve receptor sites that stimulate both thesecretion of stomach acid and smooth muscle activity in the digestivetract. Accordingly, it diminishes the volume and free acidity of gastricsecretions and controls excessive pharyngeal, tracheal, and bronchialsecretions.

Glycopyrrolate is indicated for use as adjunctive therapy in thetreatment of peptic ulcer. See PHYSICIANS' DESK REFERENCE (57th ed.,Medical Economics Co., 2003). The most frequent adverse reactions toglycopyrrolate include those that are common to anticholinergicsgenerally including, for example, xerostomia, decreased sweating,urinary hesitancy and retention, blurred vision, tachycardia,palpitations, headaches, dizziness, nausea, vomiting, nervousness, andother reactions.

Pharmacokinetic studies have not previously been conducted to evaluatethe effect of food on the pharmacokinetics of glycopyrrolate. It isdesirable to increase the oral bioavailability of a drug substance, suchas glycopyrrolate, to increase the extent of the therapeutic effect onthe user. In general, food has a variable effect on the bioavailabilityof an active agent. Drug-food interactions may result in reduced,delayed or increased systemic drug availability. See, e.g., ClinPharmacokinet 1984 September-October; 9(5):404-34. Food may interactwith a coadministered drug at the following phases: (i) before andduring gastrointestinal absorption; (ii) during distribution; (iii)during metabolism; and (iv) during elimination. See Clin Pharmacokinet1999 September; 37(2):213-55. For some drugs such as, for example,nefazadone and troglitazone, bioavailability increases with food. SeeClin Pharmacokinet 1997 October; 33(4):260-75; Clin Pharmacokinet 1999August; 37(2):91-104.

There remains a need for a method of treatment of peptic ulcer and othergastrointestinal disorders using glycopyrrolate that has increased oralbioavailability and, thus, improved efficacy following administration tohuman patients.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of the mean plasma concentration of glycopyrrolate innanograms per milliliter versus the time elapsed from administration ofa liquid glycopyrrolate dosage form (2 mg dose of 1 mg/5 mL liquidsolution). Two plots are shown for the liquid glycopyrrolate dosage formadministered under fasted and fed conditions.

FIG. 2 is a plot of the mean plasma concentration of glycopyrrolate innanograms per milliliter (semi-log) versus the time elapsed fromadministration of a liquid glycopyrrolate dosage form (2 mg dose of 1mg/5 mL liquid solution). Two plots are shown for the liquidglycopyrrolate dosage form administered under fasted and fed conditions.

BRIEF SUMMARY OF THE INVENTION

The subject of this invention is the unexpected finding thatadministration of glycopyrrolate under fasted conditions (i.e., withoutfood), increases the extent of absorption via the oral dosage form inhuman subjects.

One aspect of this invention is a method of increasing thebioavailability of glycopyrrolate in a human patient receivingglycopyrrolate therapy wherein the glycopyrrolate is contained in apharmaceutical composition, which method comprises administering atherapeutically effective amount of glycopyrrolate to the patientwithout food.

Another aspect of the invention is providing a method of increasing theextent of glycopyrrolate absorption as measured by the drugconcentration attained in the blood stream over time of a patientreceiving the drug in an oral dosage form which method comprisesadministering a therapeutically effective amount of glycopyrrolate tothe patient without food.

The invention further includes a method of increasing the oralbioavailability of glycopyrrolate to a patient receiving glycopyrrolatetherapy comprising administering to the patient a pharmaceutical tabletcomprising about 1 mg to about 10 mg of glycopyrrolate under fastedconditions, wherein the administration results in an increase of themaximum plasma concentration (C_(max)) and the extent of absorption ofglycopyrrolate at t=24 hours (AUC_(0-24hrs)) as compared to theadministration of glycopyrrolate under fed conditions.

The invention is also directed to a method for treating peptic ulcer orother gastrointestinal disorders in a patient, which comprisesadministering a therapeutically effective amount of glycopyrrolatewithout food. To this end, a patient is administered glycopyrrolate,wherein the resulting maximum plasma concentration (C_(max)) afteradministration is at least about 2.5 ng/mL.

The invention further relates to a kit comprising a pharmaceuticalcomposition comprising a therapeutically effective amount ofglycopyrrolate and a pharmaceutically acceptable carrier, prescribinginformation, and a container. The prescribing information includesadvice to a patient regarding the administration of glycopyrrolatewithout food to improve bioavailability.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to methods and compositions for thetreatment of certain gastrointestinal conditions. These conditionsinclude, but are not limited to, peptic ulcer, duodenal ulcer, dyspepsia(indigestion), gastroesophageal reflux disease (GERD), irritable bowelsyndrome (IBS), acid-related diseases of the gastrointestinal tract,bleeding of the stomach and duodenum, esophagitis (inflammation of theesophagus), and gastritis.

In addition to the treatment of gastrointestinal conditions, the methodsand compositions of the present invention are useful in the treatment ofa variety of conditions or pathologies having mild to severe symptomsthat can limit a patient's lifestyle as well as limit a patient'sability to interact and communicate with others. Such conditions andpathologies include, but are not limited to, gustatory sweating, Frey'ssyndrome, sialhorrhea (excessive drooling), hyperhidrosis, Meniere'sdisease and myasthenia gravis.

It has been discovered that glycopyrrolate can be administered to humanpatients in a regime that increases the therapeutic effectiveness ofglycopyrrolate such patients. Specifically, when administered underfasted conditions, glycopyrrolate exhibits increased oralbioavailability in patients.

Therefore, according to one aspect, the present invention provides amethod of increasing the oral bioavailability of glycopyrrolate in ahuman patient comprising administering to the patient a therapeuticallyeffective amount of glycopyrrolate under fasted conditions.

As used herein, the term “bioavailability” generally means the rate andextent to which the active ingredient is absorbed from a drug productand becomes available at the site of action. See Code of FederalRegulations, Title 21, Part 320.1 (2003 ed.). For oral dosage forms,bioavailability relates to the processes by which the active ingredientis released from the oral dosage form and moves to the site of action.Bioavailability data for a particular formulation provides an estimateof the fraction of the administered dose, for example, an oral tablet,that is absorbed into the systemic circulation.

As used herein, the terms “without food,” “fasted conditions,” and“empty stomach” are defined to mean, in general, the condition of nothaving consumed food during the period between from at least about 30minutes prior to the administration of glycopyrrolate to at least about1 hour after the administration of glycopyrrolate.

In contrast, the term “with food” is defined to mean, in general, thecondition of having consumed food during the period between from about 1hour prior to the administration of glycopyrrolate to about 2 hoursafter the administration of glycopyrrolate. Preferably, the food is asolid food with sufficient bulk and fat content that it is not rapidlydissolved and absorbed in the stomach. More preferably, the food is ameal, such as breakfast, lunch or dinner.

Advantageously, glycopyrrolate administered any time of day withoutfood. Preferably, food is not consumed during the period between from atleast about 30 minutes prior to the administration of glycopyrrolate toat least about 1 hour after the administration of glycopyrrolate.

Glycopyrrolate is preferably administered in the morning under fastedconditions. Any suitable administration time in the morning may beutilized, for example, around 8:00 a.m. More preferably, glycopyrrolateis administered in the morning without food with the patient havingfasted for at least about 10 hours. For example, glycopyrrolate isadministered at around 8:00 a.m. with the patient having fasted sincearound 10:00 p.m. the night before.

The methods of the present invention are directed to the administrationof a therapeutically acceptable amount of glycopyrrolate orpharmaceutically acceptable salt or prodrug of glycopyrrolate. Thepresent invention further contemplates the use glycopyrronium bromideand of other forms of glycopyrronium associated with other ioniccomponents, such as other salts of glycopyrronium.

Glycopyrrolate exists in four distinct stereoisometric forms due to thepresence of two chiral centers in the glycopyrrolate molecule. One ofthe two enantiomeric pairs of diastereomers of glycopyrrolate is(R,R)-glycopyrrolate and (S,S)-glycopyrrolate, and the otherenantiomeric pair is (R,S)-glycopyrrolate and (S,R)-glycopyrrolate. Theglycopyrrolate suitable for use in the present invention may be amixture of two or more of the four stereoisomers. Alternatively,glycopyrrolate may be used in the form of one isolated enantiomer.

Enantiomerically enriched glycopyrrolate may also be used.Enantiomerically enriched (S,S)-glycopyrrolate, (R,R)-glycopyrrolate,(S,R)-glycopyrrolate, and (R,S)-glycopyrrolate, and methods of theirpreparation, are described in U.S. Pat. Nos. 6,063,808, 6,204,285, PCTApplication WO 98/00109, and PCT Application WO 98/00132, allincorporated herein by reference.

In general, a suitable dose of a therapeutically effective amount ofglycopyrrolate or a pharmaceutically acceptable salt thereof foradministration to a patient will be between approximately 0.0005 to 300mg per kilogram body weight of the recipient per day, preferably betweenapproximately 0.0005 and 50 mg/kg/day, and most preferably betweenapproximately 0.001 to 10 mg/kg/day. A typical dose of a therapeuticallyeffective amount of glycopyrrolate or pharmaceutically acceptable saltthereof in human patients is about 1-100 mg/day, preferably about 2-50mg/day, and more preferably about 3-10 mg/day.

If desired, the effective daily dose of glycopyrrolate may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. The typical amount of glycopyrrolatein a unit dosage form useful in the present invention is about 1-10 mg,preferably about 1-5 mg, and most preferably about 1-2 mg. Each suchsub-dose contains a therapeutically effective amount of glycopyrrolate.

In accordance with the inventive method, glycopyrrolate may beadministered without food at multiple times per day or, alternatively,once per day. When administered at multiple times throughout the day,each individual dose contains a therapeutically effective amount ofglycopyrrolate.

A preferred dosing of a therapeutically effective amount ofglycopyrrolate is one milligram three times daily, for example, in themorning, early afternoon, and at bedtime. The bedtime dose mayoptionally be two milligrams to assure overnight control of symptoms.After the initial dosage of glycopyrrolate, an adequate dosage formaintenance of one milligram twice per day is often suitable.Alternatively, glycopyrrolate may be administered two or three timesdaily with two milligrams per dose. Preferably, with all glycopyrrolatedosing schedules, the time periods between administrations are equal.

The components of the combination which may be referred to as activeingredients may be administered for therapy to an animal (e.g., amammal), including a human, in any conventional manner. While it ispossible for the active ingredients of the combination to beadministered as the raw chemical, it is preferable to present them as apharmaceutical formulation. Pharmaceutical formulations according to thepresent invention comprise the active ingredients (that is, thecombination of glycopyrrolate or a pharmaceutically acceptable saltthereof and one or more acid suppressant agents) together with one ormore pharmaceutically acceptable carriers or excipients and optionallyother therapeutic agents. The carrier(s) must be acceptable in the senseof being compatible with the other ingredients of the formula and notdeleterious to the recipient thereof. When the individual components ofthe combination are administered separately, they are generally eachpresented as a pharmaceutical formulation.

The combinations of the invention can also include other medicinalagents, pharmaceutical agents, carriers, adjuvant diluents and otherpharmaceutical preparations known to those skilled in the art. Thoseagents are known to those skilled in the art and are generally describedas being biologically inactive and can be administered to patientswithout causing deleterious interactions with the active agents. Forexample, glycopyrrolate may be combined with other active agents for thetreatment of gastrointestinal disorders or comorbid diseases associatedwith gastrointestinal condition including adjunct therapy for thetreatment of peptic ulcers. Suitable acid suppressants includeH₂-receptor antagonists (e.g., cimetidine, famotidine, nizatidine,ranitidine) or proton pump inhibitors (e.g., omeprazole, esomeprazole,lansoprazole, pantoprazole, rabeprazole).

Examples of carriers or excipients for oral administration includecornstarch, lactose, magnesium stearate, microcrystalline cellulose andstearic acid, povidone, dibasic calcium phosphate and sodium starchglycolate. Any carrier suitable for the desired administration route iscontemplated by the present invention.

Suitable formulations include those suitable for oral, rectal, nasal,topical (including transdermal, buccal and sublingual), vaginal orparenteral (including subcutaneous, intramuscular, intravenous,intraarterial, intraperitoneal, intraspinal, and intradermal)administration. Suitable glycopyrrolate formulations useful in thepresent invention are described in WO 01/08681, incorporated herein byreference.

The formulations may be prepared by any methods well known in the art ofpharmacy, for example, using methods such as those described in Gennaroet al., Remington's Pharmaceutical Sciences (18th ed., Mack PublishingCo., 1990), especially Part 8; Pharmaceutical Preparations and theirManufacture. Such methods include the step of bringing into associationthe active ingredient with the carrier which constitutes one or moreaccessory ingredients. Such accessory ingredients include thoseconventional in the art, such as, fillers, binders, diluents,disintegrants, lubricants, colorants, flavoring agents, and wettingagents.

The combinations of the invention can provide controlled, slow release,or sustained release of the therapeutic compounds over a predeterminedperiod of time. Administration of the combination using theseformulations allows for a desired concentration of the compound to bemaintained in the bloodstream of the patient for a longer period of timethat with conventional formulations. Slow release, controlled, orsustained release formulations are known to those skilled in the art andinclude formulations such as coated tablets, pellets, capsules,dispersion of the active agents in a medium that is insoluble inphysiologic fluids, or where the release of the active agents followsdegradation of the formulation due to mechanical, chemical, or enzymaticactivity.

Preferred methods of administration include oral routes. Thecompositions of the present invention can be contained in a pill,capsule, or tablet, each containing a predetermined amount of activeingredient and preferably coated for ease of swallowing; as a powder orgranules; or as a solution or suspension. For oral administration, finepowders or granules may contain diluting, dispersing, and or surfaceactive agents and may be present in a solution or suspension in water orsyrup, capsules or sachets in the dry state, in a nonaqueous solution orsuspension wherein suspending agents may be included, or in tabletswherein binders and lubricants may be included. Components may be addedsuch as flavoring, preserving, suspending, thickening or emulsifyingagents. Such preparations are known or apparent to those skilled in theart.

Oral delivery methods are often limited by chemical and physicalbarriers imposed by the body, such as the varying pH in thegastrointestinal tract, exposure to enzymes, and the impermeability ofthe gastrointestinal membranes. Methods of the present invention fororally administering the combination may also include theco-administration of adjuvants with the compositions of the presentinvention. For example, nonionic surfactants such as polyoxyethyleneoleyl ether and n-hexadecyl polyethylene ether can be administered withor incorporated into the combinations of the present invention toartificially increase the permeability of the intestinal walls. Othermethods include the co-administration of enzymatic inhibitors with thecombinations of the present invention. The active ingredients may alsobe present as a bolus or paste or may be contained within liposomes andemulsions.

Formulations for rectal administration may be presented as a suppositoryor enema.

For parenteral administration, suitable formulations include aqueous andnon-aqueous sterile injection. The formulations may be presented inunit-dose or multi-dose containers, for example, sealed vials andampoules, and may be stored in a freeze dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for example,water, prior to use.

Formulations suitable for administration by nasal inhalation includefine dusts or mists which may be generated by means of metered dosepressurized aerosols, nebulizers, or insufflators.

When administered in the form of an aqueous liquid solution, theformulation will contain the glycopyrrolate active agent and purifiedwater. Optional components in liquid solution include suitable solvents,buffering agents, sweeteners, anti-microbial preservatives, flavoringagents, and mixtures thereof. A component of the formulation may servemore than one function. For example, a suitable buffering agent may alsoact as a flavoring agent as well as a sweetener.

Suitable solvents in the liquid solution used in the present inventioninclude, for example, sorbital, glycerin, propylene glycol, and water. Amixture of two or more solvents may optionally be used. The solvent orsolvent system is typically present in an amount of from about 1% toabout 90% by weight of the total liquid formulation.

Suitable buffering agents include, for example, citric acid, sodiumcitrate, phosphoric acid, potassium phosphate, and various other acidsand salts. A mixture of two or more buffering agents may optionally beused. The buffering agent or mixtures thereof are typically present inan amount of from about 0.001 wt. % to about 4 wt. %.

Suitable sweeteners include, for example, saccharin sodium, sucrose, andmannitol. A mixture of two or more sweeteners may optionally be used.The sweetener or mixtures thereof are typically present in an amount offrom about 0.001 wt. % to about 70 wt. %.

Suitable anti-microbial preservatives include, for example,methylparaben, propylparaben, sodium benzoate, benzalkonium chloride. Amixture of two or more preservatives may optionally be used. Thepreservative or mixtures thereof are typically present in an amount offrom about 0.0001 wt. % to about 2 wt. %.

Suitable flavoring agents may be used to the liquid solution a cherryflavor, cotton candy flavor, or other suitable flavor to make thesolution easier for a patient to ingest. The flavoring agent or mixturesthereof are typically present in an amount of from about 0.0001 wt. % toabout 5 wt. %.

The following examples further illustrate the invention but, of course,should not be construed as in any way limiting its scope.

EXAMPLE 1

A preferred liquid formulation suitable for use in the method of thepresent invention contains the following components:

Ingredient Quantity (wt. %) glycopyrrolate USP 0.02 sorbitol solution60.0 glycerin 10.0 citric acid 0.128 sodium citrate 0.064 saccharinsodium 0.05 propylene glycol 10.0 methylparaben 0.18 propylparaben 0.02cherry flavor 0.10 purified water 19.438

Another aspect of the invention is a kit comprising a pharmaceuticalcomposition comprising a therapeutically effective amount ofglycopyrrolate and a pharmaceutically acceptable carrier, prescribinginformation, and a container.

The prescribing information is generally a piece of paper that includesinstructions regarding the proper administration of glycopyrrolate. Inthe kit of the present invention, the prescribing information willinclude advice regarding the administration of glycopyrrolate withoutfood to improve bioavailability. The prescribing information will beconsistent with the methods of treatment described herein.

Such advice may be provided on the prescribing information in the formof a discussion of the increased bioavailability of glycopyrrolate iftaken on an empty stomach as compared with its use if taken with food.The advice may optionally include pharmacokinetic data comparing theadministration of glycopyrrolate taken under fasted and fed conditions.The advice may alternatively be provided in the form of instructions totake glycopyrrolate under fasted conditions. Such instructions may beprovided in writing with the prescribing information alone or incombination with a discussion of the relative bioavailability ofglycopyrrolate administered without and with food.

The pharmaceutical composition will be contained in any suitablecontainer capable of holding and dispensing the dosage form and whichwill not significantly interact with the composition and will further bein physical relation with the prescribing information containing adviceregarding the preferred administration of glycopyrrolate under fastedconditions. The container may be, for example, a cardboard box orplastic vial. Alternatively, the glycopyrrolate composition may beprovided in individual unit dosage forms, such as plastic strips sealedwith aluminum foil. Such unit dosage forms may optionally be furtherpackaged in a box, vial or other suitable container along with theprescribing information. When glycopyrrolate is to be administered witha second active agent, the two pharmaceutical dosage forms may be placedin the same or separate containers.

The prescribing information may be associated with the container by anymeans that maintain a physical proximity of the two. For example, theymay both be contained in a packaging material such as a box or plasticshrink wrap. Alternatively, the prescribing information may be bonded tothe container such as with suitable glue or other bonding or holdingmeans such that the prescribing information is not obscured.

EXAMPLE 2

The effect of food on glycopyrrolate absorption in human patients wasidentified in a study designed to compare the bioavailability of 2 mg ofglycopyrrolate in a liquid formulation administered to healthyvolunteers with and without food. An object of the study was to evaluatethe relative bioavailability of glycopyrrolate when administered tohuman subjects with and without food.

An open-label, randomized, crossover trial in healthy subjects wasconducted over a 16-day treatment period which includes three (3) dosingperiods. There was a one week washout period between each dose.

The two study drug treatments were as follows:

-   -   Treatment A—glycopyrrolate liquid 2 mg (10 mL dose of 1 mg per 5        mL solution) administered without food; and    -   Treatment B—glycopyrrolate liquid 2 mg (10 mL dose of 1 mg per 5        mL solution) administered with food.

A single center, single dose, open label, two-period crossover trial wasdevised for study in healthy subjects. A total of 39 subjects (25 malesand 14 females) were enrolled and dosed. Each administration was asingle oral dose of 2 mg of glycopyrrolate liquid either without food(Group A) or with food (Group B). The plasma of subjects in the studywere assayed and used for pharmacokinetic analysis.

The study drug was administered according to Treatment A (without food)and Treatment B (with food) as follows.

Treatment A—without Food

10 mL of liquid containing 2 mg of glycopyrrolate (1 mg/5 mL) in theliquid formulation described in Example 1 was administered by an oralsyringe. The glycopyrrolate liquid formulation was administered with 180mL (6 fluid ounces) of water.

Subjects will have fasted from about 10 p.m. the day before dosing.Dosing occurred at about 8:00 a.m. Fasting continued for four (4) hoursafter the dosing. Water was allowed to be taken ad libitum from 2 hoursafter dosing.

Blood samples for pharmacokinetic analysis were taken immediately priorto dosing and at the following times after dosing: 0.25, 0.5, 1, 1.5, 2,2.5, 3, 4, 6, 8, 12, 16, and 24 hours.

Treatment B—with Food

10 mL of liquid containing 2 mg of glycopyrrolate (1 mg/5 mL) in theliquid formulation described in Example 1 was administered by an oralsyringe. The glycopyrrolate liquid formulation was administered with 180mL (6 fluid ounces) of water. Breakfast was given to the subjects inGroup A 30 minutes prior to dosing and eaten within a 30 minute period.The dose of glycopyrrolate was administered to the subjects immediately(i.e., within 5 minutes) after completion of breakfast.

Subjects will have fasted from about 10 p.m. the day before dosing. Ahigh fat, high calorie breakfast was eaten at about 7:30 a.m. Dosingoccurred immediately following completion of the meal at about 8:00 a.m.The dose was administered at the same time for an individual subject. Nofurther food was permitted until lunch which did not occur until atleast four (4) hours post dose. Water was allowed to be taken ad libitumfrom 2 hours after dosing.

The breakfast consisted of the following:

-   -   2 eggs (with one tablespoon butter for cooking eggs);    -   2 strips of bacon;    -   2 slices of toast with butter (with one tablespoon butter);    -   4 ounces of hash brown potatoes; and    -   1 glass whole milk (8 fluid ounces).

Blood samples for pharmacokinetic analysis were taken immediately priorto dosing and at the following times after dosing: 0.25, 0.5, 1, 1.5, 2,2.5, 3, 4, 6, 8, 12, 16, and 24 hours.

All pharmacokinetic parameters were analyzed by noncompartmentalmethods. The following PK parameters were calculated for the two PKprofiles and are defined as follows:

-   -   T_(max) Time to maximum concentration;    -   C_(max) Observed maximum concentration;    -   k_(el) Slope of terminal linear portion of concentration/time        curve;    -   t_(1/2) Apparent elimination half-life;    -   AUC_(0-t) Area under the curve to the concentration at time t as        measured by the trapezoidal rule;    -   AUC_(0-24 hrs) Area under the curve to the concentration at time        t=24 hours; and    -   AUC_(0-∞) The AUC value extrapolated to infinity calculated as        AUC_(0-∞)=AUC_(0-24 hrs)+C_(24 hrs)/k_(el) where C_(24 hrs) is        the concentration measured at 24 hours after administration.

Pharmacokinetic parameters were log-transformed by analysis and assessedusing SAS® Least Square Means derived from a three-way analysis ofvariance (ANOVA) fitting effects for subject, treatment, and period.Treatments comparisons were made by calculating the difference and 95%confidence intervals (CIs) of the difference of the log SAS Least SquareMeans between parameters for the respective treatments. The differencesand CIs about the differences were back-transformed for reportingpurposes.

The individual test results for plasma glycopyrrolate parametersAUC_(0-∞) (ng*hr/mL), AUC_(0-24 hrs) (ng*hr/mL), C_(max) (ng/mL), andT_(max) (hr) are summarized in Tables I-IV, respectively. Thepharmacokinetic parameters k_(el) and t_(1/2) are estimated fordescriptive purposes.

TABLE I Comparison of AUC_(0-∞) (ng * hr/mL) and Ln AUC_(0-∞)Administered Without Food (Group A) v. Administered With Food (Group B)Group A Group B Subject fasted fed Difference Ratio Ln Ratio Number(ng/mL) (ng/mL) (A − B) (A/B) (Ln A/B) 001 3.3609 0.6642 2.6967 5.0601.6214 002 0.6579 0.2815 0.3764 2.337 0.8489 003 1.5650 0.3288 1.23624.760 1.5602 004 4.5090 0.8646 3.6444 5.215 1.6516 005 0.6368 0.34380.2930 1.852 0.6164 006 1.7365 0.3274 1.4091 5.304 1.6684 007 0.64830.3568 0.2915 1.817 0.5972 008 1.5432 0.4953 1.0479 3.116 1.1364 0092.4073 0.4374 1.9699 5.504 1.7054 010 0.8591 0.3496 0.5095 2.457 0.8991011 0.8860 0.5555 0.3305 1.595 0.4668 012 1.2341 0.5596 0.6745 2.2050.7909 013 3.2796 0.4734 2.8062 6.928 1.9355 014 2.9265 0.5345 2.39205.475 1.7002 015 0.7822 0.4643 0.3179 1.685 0.5216 016 1.7861 0.46191.3242 3.867 1.3524 017 — — — — — 018 1.1544 0.4513 0.7031 2.558 0.9392019 1.5328 0.4736 1.0592 3.236 1.1745 020 1.1659 0.1557 1.0102 7.4882.0133 021 1.7534 0.5257 1.2277 3.335 1.2046 022 2.3768 — — — — 0233.1990 0.3830 2.8160 8.352 2.1226 024 0.9916 0.4602 0.5314 2.155 0.7677025 1.0543 0.3292 0.7251 3.203 1.1640 026 1.0993 0.5757 0.5236 1.9100.6468 027 1.3869 0.3414 1.0455 4.062 1.4018 028 2.6432 0.4192 2.22406.305 1.8414 029 — — — — — 030 3.5489 0.6786 2.8703 5.230 1.6544 0311.3621 0.3193 1.0428 4.266 1.4507 032 0.8257 0.4332 0.3925 1.906 0.6450033 1.7290 — — — — 034 4.7688 0.6349 4.1339 7.511 2.0164 035 0.88390.4115 0.4724 2.148 0.7645 036 1.2865 0.5715 0.7150 2.251 0.8114 1172.2357 0.5499 1.6858 4.066 1.4026 129 2.4764 0.4979 1.9785 4.974 1.6042133 0.6692 0.3633 0.3059 1.842 0.6109 N 37 35 35 35 35 Mean 1.80980.4592 1.3367 3.885 1.2374 Std Dev 1.0878 0.1347 1.0354 1.921 0.5001 %CV 60.1 29.3 77.5 49.4 40.4 Median 1.5328 0.4602 1.0455 3.335 1.2046Minimum 0.6368 0.1557 0.2915 1.595 0.4668 Maximum 4.7688 0.8646 4.13398.352 2.1226

TABLE II Comparison of AUC_(0-24 hrs) (ng * hr/mL) and Ln AUC_(0-24 hrs)Administered Without Food (Group A) v. Administered With Food (Group B)Group A Group B Subject fasted fed Difference Ratio Ln Ratio Number(ng/mL) (ng/mL) (A − B) (A/B) (Ln A/B) 001 3.2789 0.5337 2.7452 6.1441.8154 002 0.6015 0.1302 0.4713 4.620 1.5304 003 1.5151 0.2746 1.24055.517 1.7079 004 4.3370 0.7616 3.5754 5.695 1.7395 005 0.6174 0.13940.4780 4.429 1.4882 006 1.7029 0.2800 1.4229 6.082 1.8053 007 0.54860.2865 0.2621 1.915 0.6496 008 1.5023 0.4603 1.0420 3.264 1.1829 0092.3508 0.3516 1.9992 6.686 1.9000 010 0.8025 0.2762 0.5263 2.906 1.0666011 0.7598 0.4083 0.3515 1.861 0.6211 012 1.1953 0.4710 0.7243 2.5380.9313 013 3.2238 0.4053 2.8185 7.954 2.0737 014 2.8080 0.4643 2.34376.048 1.7997 015 0.6496 0.4193 0.2303 1.549 0.4378 016 1.7377 0.38611.3516 4.501 1.5042 017 — — — — — 018 1.0881 0.4005 0.6876 2.717 0.9995019 1.4534 0.3041 1.1493 4.779 1.5643 020 1.0868 0.1155 0.9713 9.4102.2417 021 1.6919 0.4643 1.2276 3.644 1.2931 022 2.3242 0.5343 1.78994.350 1.4702 023 3.0914 0.3348 2.7566 9.234 2.2228 024 0.9414 0.32130.6201 2.930 1.0750 025 1.0261 0.2838 0.7423 3.616 1.2853 026 1.04230.5235 0.5188 1.991 0.6886 027 1.3460 0.2810 1.0650 4.790 1.5665 0282.5938 0.3625 2.2313 7.155 1.9679 029 — — — — — 030 3.4602 0.6097 2.85055.675 1.7361 031 1.3102 0.2389 1.0713 5.484 1.7019 032 0.7319 0.28730.4446 2.548 0.9351 033 1.6329 — — — — 034 4.5894 0.5466 4.0428 8.3962.1278 035 0.7945 0.3695 0.4250 2.150 0.7656 036 1.2253 0.4947 0.73062.477 0.9070 117 2.1502 0.5077 1.6425 4.235 1.4434 129 2.4003 0.45081.9495 5.325 1.6723 133 0.6238 0.3234 0.3004 1.929 0.6569 N 37 36 36 3636 Mean 1.7361 0.3834 1.3556 4.571 1.4048 Std Dev 1.0693 0.1368 1.00082.154 0.4988 % CV 61.6 35.7 73.8 47.1 35.5 Median 1.4534 0.3778 1.06824.465 1.4962 Minimum 0.5486 0.1155 0.2303 1.549 0.4378 Maximum 4.58940.7616 4.0428 9.410 2.2417

TABLE III Comparison of C_(max) (ng/mL) and Ln C_(max) AdministeredWithout Food (Group A) v. Administered With Food (Group B) Group A GroupB Subject fasted fed Difference Ratio Ln Ratio Number (ng/mL) (ng/mL) (A− B) (A/B) (A/B) 001 0.5210 0.0951 0.4259 5.478 1.7008 002 0.0975 0.02870.0688 3.397 1.2230 003 0.3780 0.0567 0.3213 6.667 1.8971 004 0.83500.5430 0.2920 1.538 0.4303 005 0.1560 0.0301 0.1259 5.183 1.6453 0060.2920 0.0540 0.2380 5.407 1.6878 007 0.1220 0.1120 0.0100 1.089 0.0855008 0.2030 0.0575 0.1455 3.530 1.2614 009 0.5800 0.0735 0.5065 7.8912.0657 010 0.1630 0.0574 0.1056 2.840 1.0437 011 0.1560 0.0748 0.08122.086 0.7350 012 0.2540 0.0871 0.1669 2.916 1.0703 013 0.4470 0.08320.3638 5.373 1.6813 014 0.3820 0.0583 0.3237 6.552 1.8798 015 0.06970.0625 0.0072 1.115 0.1090 016 0.3050 0.0845 0.2205 3.609 1.2836 017 — —— — — 018 0.2340 0.1090 0.1250 2.147 0.7640 019 0.1940 0.0570 0.13703.404 1.2248 020 0.2650 0.0386 0.2264 6.865 1.9265 021 0.2750 0.05510.2199 4.991 1.6076 022 0.3730 0.0684 0.3046 5.453 1.6962 023 0.83400.0765 0.7575 10.902 2.3889 024 0.2150 0.0573 0.1577 3.752 1.3223 0250.1920 0.0669 0.1251 2.870 1.0543 026 0.2140 0.0891 0.1249 2.402 0.8762027 0.1950 0.0556 0.1394 3.507 1.2548 028 0.6680 0.0822 0.5858 8.1272.0951 029 — — — — — 030 0.5450 0.1010 0.4440 5.396 1.6857 031 0.23500.0494 0.1856 4.757 1.5596 032 0.1550 0.0599 0.0951 2.588 0.9507 0330.2620 — — — — 034 0.5670 0.0799 0.4871 7.096 1.9596 035 0.2020 0.09830.1037 2.055 0.7202 036 0.2740 0.0937 0.1803 2.924 1.0730 117 0.36800.0789 0.2891 4.664 1.5399 129 0.3010 0.0670 0.2340 4.493 1.5024 1330.2280 0.0730 0.1550 3.123 1.1389 N 37 36 36 36 36 Mean 0.3178 0.08380.2356 4.339 1.3372 Std Dev 0.1895 0.0813 0.1658 2.180 0.5394 % CV 59.697.0 70.4 50.2 40.3 Median 0.2620 0.0707 0.1830 3.681 1.3029 Minimum0.0697 0.0287 0.0072 1.089 0.0855 Maximum 0.8350 0.5430 0.7575 10.9022.3889

TABLE IV Comparison of T_(max) (hr) Administered Without Food (Group A)v. Administered With Food (Group B) Group A Group B Subject fasted fedDifference Ratio Number (hr) (hr) (A − B) (A/B) 001 4.000 2.000 2.0002.000 002 2.500 1.500 1.000 1.667 003 2.500 2.000 0.500 1.250 004 2.5002.500 0.000 1.000 005 3.000 2.020 0.980 1.485 006 6.000 2.000 4.0003.000 007 2.500 2.500 0.000 1.000 008 4.000 6.080 −2.080 0.658 009 2.5002.500 0.000 1.000 010 2.500 2.000 0.500 1.250 011 0.500 3.000 −2.5000.167 012 3.000 3.000 0.000 1.000 013 4.000 2.500 1.500 1.600 014 4.0002.500 1.500 1.600 015 4.000 4.000 0.000 1.000 016 2.500 2.500 0.0001.000 017 — — — — 018 2.500 2.000 0.500 1.250 019 2.500 2.500 0.0001.000 020 2.520 1.500 1.020 1.680 021 3.000 6.000 −3.000 0.500 022 4.0002.500 1.500 1.600 023 4.000 2.000 2.000 2.000 024 2.620 2.000 0.6201.310 025 4.000 1.500 2.500 2.667 026 2.530 2.000 0.530 1.265 027 2.5303.000 −0.470 0.843 028 2.500 2.500 0.000 1.000 029 — — — — 030 4.0002.000 2.000 2.000 031 4.000 1.000 3.000 4.000 032 2.000 1.500 0.5001.333 033 3.000 — — — 034 6.000 4.000 2.000 1.500 035 2.500 2.000 0.5001.250 036 2.500 4.000 −1.500 0.625 117 4.000 3.000 1.000 1.333 129 2.0004.000 −2.000 0.500 133 2.030 2.000 0.030 1.015 N 37 36 36 36 Mean 3.1012.600 0.504 1.371 Std Dev 1.075 1.120 1.482 0.725 % CV 34.7 43.1 294.252.9 Median 2.530 2.500 0.500 1.250 Minimum 0.500 1.000 −3.000 0.167Maximum 6.000 6.080 4.000 4.000

The results of the pharmacokinetic analysis of the subjects' mean plasmaglycopyrrolate concentration over time administered under fasted and fedconditions are set forth in FIGS. 1 and 2. FIG. 1 is a plot of the meanconcentration (ng/mL) and FIG. 2 is a plot of a semi-log of the meanconcentration (ng/mL). As the figures illustrate, the C_(max) and AUCare significantly greater for glycopyrrolate administered without food.

Based on arithmetic means, the mean AUC_(0-24 hrs) for glycopyrrolateadministered under fasted conditions was 1.7361±1.069 ng*hr/mL and forglycopyrrolate administered under fed conditions was 0.3834±0.1368ng*hr/mL. Thus, the mean AUC_(0-24 hrs) for Group A (fasted) was morethan 4.5 times higher than the mean AUC_(0-24 hrs) for Group B (fed).

The results for AUC extrapolated to infinity were similar. The meanAUC_(0-∞) for glycopyrrolate administered under fasted conditions was1.8098±1.0878 ng*hr/mL. For glycopyrrolate administered under fedconditions, the mean AUC_(0-∞) was 0.3834 ng*hr/mL±0.1368. The meanAUC_(0-∞) for Group A (fasted) was more than 4.7 times higher than themean AUC_(0-∞) for Group B (fed).

The mean maximum plasma concentration C_(max) of glycopyrrolate was0.3178±0.1895 ng/mL for subjects in Group A (administration withoutfood) and 0.0838±0.0813 ng/mL for subjects in group B (administrationwith food). The mean C_(max) for Group A (fasted) was about 3.8 timesgreater than the mean C_(max) for Group B (fed).

The food effect on the pharmacokinetic parameters of glycopyrrolatefollowing the administration of 2 mg of the liquid glycopyrrolateformulation (10 mL of 1 mg/5 mL liquid solution) was appreciable.

Table V summarizes the results of the analyses performed on thepharmacokinetic parameters obtained from the fasted and fed states. LSis an abbreviation for least squared.

TABLE V Plasma Glycopyrrolate Pharmacokinetic Parameters - Without Food(Group A) v. With Food (Group B) LS Mean LS Mean Group A Group B 95%fasted fed Ratio Confidence Parameter (N subjects) (N subjects) (A − B)Interval Ln AUC_(0-24 hrs) 0.41704 −0.98781  4.075 [3.4102; (37) (36)4.8692] Ln AUC_(0-∞) 0.47407 −0.76683  3.459 [2.9175; (37) (35) 4.1003]Ln C_(max) 1.26674 −2.60398  3.809 [3.1392; (37) (36) 4.6205]AUC_(0-24 hrs) 1.84116 0.48561 3.791 [3.1347; (ng * hr/mL) (37) (36)4.4482] AUC_(0-∞) 1.93908 0.60265 3.218 [2.6754; (ng * hr/mL) (37) (35)3.7598] C_(max) 0.33727 0.10171 3.316 [2.7462; (ng/mL) (37) (36) 3.8855]T_(max) 3.15163 2.64802 1.190 [1.0126; (hr) (37) (36) 1.3678] k_(el)0.26358 0.22831 1.154 [0.9906; (1/hr) (37) (35) 1.3183] t_(1/2) 2.981443.25297 0.917 [0.7416; (hr) (37) (35) 1.0915]

With a 5% significance level, the ANOVA detected statisticallysignificant differences between glycopyrrolate fasted and fed conditionsfor Ln-transformed AUC_(0-24hrs), AUC_(0-∞), and C_(max) as well as foruntransformed AUC_(0-24hrs), AUC_(0-∞), and C_(max).

The ratio (A/B) of least-square means for AUC_(0-24hrs), AUC_(0-∞), andC_(max) were 379.1%, 321.8%, and 331.6%, respectively, demonstratingthat glycopyrrolate administered without food increased the extent ofabsorption.

In sum, the administration of glycopyrrolate without food increases theextent of absorption of a glycopyrrolate liquid solution whenadministered as a single 2 mg dose (10 mL of 1 mg/5 mL liquid solution).The bioavailability of a glycopyrrolate liquid solution increased whenadministered without food as compared to the administration ofglycopyrrolate with food.

For any suitable pharmaceutical dosage form containing a therapeuticallyeffective amount of glycopyrrolate, the C_(max) following administrationunder fasted conditions is typically at least about 2.5 ng/mL, andpreferably at least about 3.0 ng/mL. The ratio of C_(max) forglycopyrrolate (in any dosage form) administered without food to C_(max)following administration with food is generally greater than about 1.1,preferably greater than about 2.8, and more preferably greater thanabout 3.8.

The AUC_(0-24 hrs) and AUC_(0-∞) for glycopyrrolate (in anypharmaceutical dosage form) are typically greater than about 0.8ng*hr/mL following administration without food, preferably at leastabout 1.0 ng*hr/mL, and more preferably at least about 1.7 ng*hr/mL. Theratio of AUC_(0-24 hrs) and AUC_(0-∞) for glycopyrrolate (in any dosageform) administered without food to AUC_(0-24 hrs) and AUC_(0-∞)following administration with food is generally greater than about 1.8,preferably greater than about 4.5, and more preferably greater thanabout 5.5.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

1. A method of treating sialorrhea in a human patient, which comprisesorally administering about 1 mg to about 10 mg of glycopyrrolate in aliquid solution to the human patient under fasted conditions, whereinthe administration of glycopyrrolate under fasted conditions results inan increase of the maximum plasma concentration (C_(max)) and the extentof absorption of glycopyrrolate at t=24 hours (AUC_(0-24hrs)) ascompared to the administration of glycopyrrolate under fed conditions,and wherein the ratio of C_(max) following administration without foodto C_(max) following administration with food is greater than 1.1, andwherein the ratio of AUC_(0-24hrs) following administration without foodto AUC_(0-24hrs) following administration with food is greater than 1.8.2. The method of claim 1, wherein the liquid solution is an aqueousliquid solution.
 3. The method of claim 2, wherein the aqueous liquidsolution further comprises at least one ingredient selected from thegroup consisting of solvents, buffering agents, sweeteners,anti-microbial preservatives, flavoring agents, and mixtures thereof. 4.The method of claim 3, wherein the solvent is selected from the groupconsisting of sorbital, glycerin, propylene glycol, water, and mixturesthereof, the buffering agent is selected from the group consisting ofcitric acid, sodium citrate, phosphoric acid, potassium phosphate, andmixtures thereof, the sweetener is selected from the group consisting ofsaccharin sodium, sucrose, mannitol, and mixtures thereof, and theanti-microbial preservative is selected from the group consisting ofmethylparaben, propylparaben, sodium benzoate, benzalkonium chloride,and mixtures thereof.
 5. The method of claim 1, wherein the aqueousliquid solution comprises a therapeutically effective amount ofglycopyrrolate, purified water, sorbitol, glycerin, citric acid, sodiumcitrate, propylene glycol, methylparaben, and propylparaben.
 6. Themethod of claim 1, wherein the therapeutically effective amount ofglycopyrrolate is about 1 mg to about 2 mg.
 7. The method of claim 1,wherein the ratio of C_(max) following administration without food toC_(max) following administration with food is greater than 2.8, andwherein the ratio of AUC_(0-24hrs) following administration without foodto AUC_(0-24hrs) following administration with food is greater than 4.5.